PROJECT SUMMARY Anhedonia, or loss of interest or pleasure in usual activities, is characteristic of depression, some types of anxiety, as well as substance abuse and schizophrenia. Anhedonia is a predictor of poor long term outcomes, including suicide, and poor treatment response. Extant psychological and pharmacological treatments are relatively ineffective for anhedonia. Thus, there is an unmet therapeutic need for this high-risk symptom. Recent advances in affective neuroscience have elucidated processes that may underlie anhedonia and should be targeted in therapy. Specifically, anhedonia is associated with deficits in the appetitive reward system, including (1) reward approach-motivation, (2) initial responsiveness to reward attainment, and (3) learning of reward. We have developed a novel transdiagnostic psychosocial treatment for anhedonia, Positive Affect Treatment (PAT), designed to improve deficits in reward sensitivity. In our pilot study of 61 depressed or anxious and functionally impaired individuals we found a strong preliminary efficacy signal and evidence for treatment specificity. Specifically, PAT led to significant improvements in symptoms of anhedonia, depression and anxiety and was more effective for individuals with anhedonia at baseline than a treatment designed to reduce negative affect. The proposed application uses an experimental therapeutics approach to elucidate whether reward approach- motivation, initial responsiveness to reward attainment or reward learning change with PAT (i.e., target engagement) in the R61 phase, and to evaluate whether changes in reward sensitivity mediate outcomes from PAT in the R33 phase. In the R61 phase, 68 individuals with anhedonia who are anxious or depressed and functionally impaired will be randomized to single-dose PAT (15 weekly sessions) or double dose PAT (PAT- DD, 30 twice-weekly sessions). Physiological, behavioral, and self-report measures of reward approach- motivation, initial reward responsiveness, and learning will be assessed repeatedly. Outcomes include clinician and self-report measures of anhedonia and ecologically valid measures of functional impairment (i.e., physical activity and social interaction). Progression to R33 depends on post-treatment average anhedonia scores that are within 1 SD of the norm, and significant (effect size > .8) pre- to post-treatment changes in reward approach- motivation, initial responsiveness to attainment or learning, which covary significantly with anhedonia over treatment. The treatment dose that produces significantly greater pre- to post-treatment change in one or more target measures will be carried forward to R33. In the R33 phase, 100 individuals will be randomized to PAT (or PAT-DD) or to Negative Affect Treatment; the latter designed to reduce threat sensitivity. Indices of reward sensitivity (from R33 phase) and threat sensitivity will be evaluated as mediators of PAT and moderated mediation will be tested by comparing reward sensitivity mediation in PAT vs NAT. If successful, PAT will offer a viable and effective treatment for individuals with anhedonia, and the results will elucidate the mechanisms responsible for the effectiveness of this novel treatment.